It has been conventionally known that arachidonic acid metabolites, prostaglandin E.sub.2 (PGE.sub.2), prostaglandin I.sub.2 (PGI.sub.2) and thromboxane B.sub.2 (TXB.sub.2) are deeply involved in inflammations. An important enzyme in this arachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase which produces prostaglandin H.sub.2 (PGH.sub.2) from arachidonic acid via prostaglandin G.sub.2 (PGG.sub.2), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
With respect to COX-1, cDNA cloning was performed in 1988 and its primary structure and induction by various factors have been clarified [Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165:888-894 (1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083:1-17 (1991); DeWitt, D. L.: Biochim. Biophys. Acta, 1083:121-134 (1991)]. On the other hand, the existence of an isozyme of COX-1, namely, COX-2, was suggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem., 267:21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88:2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem., 266:12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA, 89:7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester, lipopolysaccharide (LPS) and the like, and the relationship with inflammation and bronchial asthma has been inferred.
COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE.sub.2 and PGI.sub.2, which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused. With regard to a symptom associated with a decrease in renal blood flow, in general terms, the renal blood flow can be increased by promoting the production of vasodilative PGE.sub.2 in the body, thereby to appropriately maintain glomerular filtration rate. However, if the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
On the other hand, COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
Currently, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen and naproxen have been widely used in clinical situations. Most of these NSAIDs are anti-inflammatory drugs which selectively inhibit cyclooxygenase (COX) and are associated with side-effects such as disorders in the digestive tract. Such side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
It is therefore expected that a selective inhibition of COX-2, which is specifically induced at the inflammatory sites, would enable provision of an anti-inflammatory agent free of side-effects such as disorders in the digestive tract (e.g., ulcer).
There have recently been presented various reports on anti-inflammatory drugs having selective COX-2 inhibitory activity, which aim at reducing side-effects such as disorders in the digestive tract.
For example, WO94/15932 discloses, as COX-2 inhibitors, 5-membered cyclic compounds having one hetero atom, such as thiophene, furan and pyrrole, which are specifically exemplified by 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, these compounds are characterized by aryl or heteroaryl at the 3-position or 4-position of thiophene, and fail to suggest the compounds of the present invention.
Moreover, various reports deal with anti-inflammatory drugs having cyclooxygenase-inhibitory action, prostaglandin synthesis-inhibitory action or thromboxane A.sub.2 synthesis-inhibitory action.
For example, Japanese Patent Unexamined Publication No. 141261/1991 discloses pyrazole derivatives such as ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate; Japanese Patent Unexamined Publication No. 183767/1982 discloses thiazole derivatives such as 2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole; and Japanese Patent Unexamined Publication No. 58981/1985 discloses thiazole derivatives such as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. These publications mention that they are useful as anti-inflammatory drugs, whereas they do not disclose if they have selective inhibitory action on COX-2 to reduce side-effects, or any suggestion of it.
There are a number of reports on compounds such as those of the present invention which include oxazole derivatives or thiazole derivatives.
For example, U.S. Pat. No. 4,632,930 discloses alkyl-aryloxazole such as 5-cyclohexyl-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluoromethy l)oxazole-2-methanol. Yet, the compounds disclosed therein are effective for hypertension and their usefulness as anti-inflammatory drugs or any suggestion to that effect are not included.
Japanese Patent Application under PCT laid-open under Kohyo No. 500054/1984 discloses oxazole derivatives having heteroaryl at one of the 4-position and 5-position of oxazole ring, carbon ring aryl at the other position, and carboxy, ester or amidized carboxy via lower alkylene at the 2-position thereof, such as ethyl 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese Patent Application under PCT laid-open under Kohyo No. 500055/1984 discloses imidazole derivatives having heteroaryl and/or carbon ring aryl at the 4-position or 5-position of imidazole ring and having formyl or acetalized formyl via lower alkylene at the 2-position thereof, such as 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal. As is evident from the disclosure therein, however, these compounds are mainly characterized by the substituent via lower alkylene at the 2-position, so that they are not suggestive of the compound of the present invention. In addition, these compounds are effective as dermal antiphlogistic or mucosal antiphlogistic for inflammatory dermal diseases, but do not teach or even suggest that they have selective inhibitory action on COX-2.
Japanese Patent Unexamined Publication No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamid e; and Japanese Patent Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications do not disclose as to the substitution of the 4-position or 5-position of thiazole ring or imidazole ring with phenyl substituted by aminosulfonyl, lower alkylaminosulfonyl, lower alkylsulfonylamino or lower alkylsulfonyl.
WO94/27980 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2 inhibitors. However, the compounds described in this publication are, from the overall description in the specification, mainly characterized by 4-fluorophenyl and 4-methylsulfonylphenyl at the 4-position and 5-position of oxazole ring, and do not suggest the compounds having specific substituents in combination, as in the present invention. In addition, the superior selective inhibition of COX-2 of the present invention cannot be envisaged from the compound of this publication.